The neuronal isozyme of nitric oxide synthase (nNOS) catalyzes the oxidation of L-arginine to L-citrulline in the brain, generating small molecule nitric oxide (NO), a critical biological signaling molecule for neurotransmission. Significant research has shown that the overexpression of nNOS is implicated in various neurological diseases, including Parkinson's, Alzheimer's, Huntington's diseases, and neuronal damage due to stroke. Thus, selective inhibition of nNOS over its closely related isoforms, endothelial NOS (eNOS) and inducible NOS (iNOS), can provide a promising strategy in developing therapeutics for the treatment of neurodegenerative diseases.
A significant amount of research has been devoted to the development of nNOS selective inhibitors. Chiral pyrrolidine-based inhibitors (1 and 2, FIG. 1) have excellent potency (Ki=85 and 15 nM, respectively) and high selectivity for nNOS over eNOS (1000- and 2100-fold, respectively) and iNOS (110-and 630-fold, respectively). However, results from animal studies indicate that these inhibitors do not optimally penetrate the blood brain barrier (BBB), and such results tend to impede application of the compounds as candidates for treatment of neurodegenerative diseases. It was reasoned that the multiple nitrogen atoms on compounds 1 and 2 were positively charged at physiological pH, which decreased penetration across the BBB by passive diffusion. Moreover, the syntheses of 1 and 2 are complicated and somewhat impractical for large scale preparation and structure-activity relationship optimization.